PROJECT SUMMARY/ABSTRACT Epigenomic features centrally underpin cardiovascular health. Among these, DNA methylation has emerged as a stable, but not immutable, chromatin modification that can be associated with gene expression but yet decorates non-genic regions of the genome, influencing cellular function by means other than transcription at the locus it occurs. In this grant we seek to determine whether these epigenomic marks can serve to predict?prior to the development of severe complications?heart failure, and to explore the underlying mechanisms of epigenomic resilience to cardiovascular disease. Rather than studying the disease process, we see to understand why some individuals develop heart failure whereas others do not. Our preliminary work in mouse models shows that DNA methylation in the heart of mice correlates with the severity of disease prior to the exposure to environmental stress (e.g. isoproterenol). Following up on this initial observation, we have now characterized DNA methylomes in a panel of inbred and recombinant inbred mouse strains, allowing us to explore the basic principles of how DNA methylation interacts with genetic variation to influence cardiovascular resilience. We now seek to translate this phenomenon to humans, identifying multi- locus epigenomic risk metrics for heart failure that distinguish resilient individuals from those more susceptible to cardiovascular complications over time. These metrics will be the basis for a new class of precision prognostic and diagnostic tools in heart failure. Our research team has initiated an IRB-approved clinical program to measure epigenetic factors in the blood of patients undergoing cardiac surgery, linking these factors to clinical data through an innovative data- mining platform that interrogates electronic medical records. As of February 2019, we have enrolled ~250 patients and performed bisulfite sequencing on 110 of them (remaining patients? samples in process). Moving forward, independent of this application, we continue to expand this cohort to include a representative sampling of the adult population in the Los Angeles region. The hypothesis we will test in this grant is that DNA methylation mechanistically underpins differential resilience to cardiac pathology and is a source of a novel class of biomarkers for human heart failure.